Continuous monitoring of the blood glucose concentration, in which measuring values are obtained every few minutes, for example, are known in the prior art under the term of “continuous monitoring”. The prior art discloses delivering of the insulin administrations required for the treatment of diabetes at optimal time and at optimal dosages in order to keep the blood glucose levels within narrow limits at all times similar to the case of a healthy person.
The blood glucose concentration of a patient is of extreme significance in medicine. Studies have shown that extremely severe long-term aftereffects of diabetes mellitus (going blind due to retinopathy, for example) can be prevented by carefully monitoring the blood glucose level and keeping it within narrow limits.
Methods, in which blood glucose concentration measuring values are obtained by continuous monitoring, are advantageous in this context in that an increase in the blood glucose concentration beyond a critical value can be counteracted in a timely fashion by the administration of insulin. In particular, the measuring values can be used as the basis for predictions of a future blood glucose concentration for a period of up to half an hour such that an increase in the blood glucose concentration can be prevented by timely administration of insulin.
Although diabetic diseases are widespread and cause serious damage, early and reliable diagnosis continues to be associated with considerable difficulties. Though overweight is known to be a risk factor for a diabetic disease, a reliable identification of pre-type 2 diabetics is not feasible as a rule.
The testing of persons suspected of bearing an increased risk of a type 2 diabetes disease through the so-called glucose clamp technique is a resource-consuming method for determining insulin resistance and therefore is done in specialized facilities only. A glucose clamp involves that the blood glucose concentration of a patient is set to an elevated value by means of a glucose infusion (e.g. to 125 mg/dl) and this value is kept as constant as possible by continuing the glucose infusions. The glucose infusion rate required to do so is a measure of how rapidly elevated blood glucose values can be lowered by increased insulin release by the body. If only a low glucose infusion rate is determined in a glucose clamp, it is taken as an indication of insulin resistance, e.g. the effect of insulin is clearly limited in extent. Insulin resistance often precedes the manifestation of type 2 diabetes by years. Recognized on time, insulin resistance can be managed by appropriate changes in the daily habits, such as e.g. quantity and composition of nutrition, and/or insulin sensitizers and the manifestation of diabetic disease can be prevented.
However, a serious disadvantage of a diagnosis based on a glucose clamp is related to the fact that adipose patients, for example, show increased insulin resistance, though this usually does not deteriorate any further, i.e. no pre-type 2 diabetes-status is manifest. In the latter case, there would be no indication for preventative treatment of type 2 diabetes both in terms of pharmacoeconomics and the inherent risks of any pharmacotherapy.
Reliable selection of the patients with a high risk of diabetes is not feasible by means of a glucose clamp. Though suitable therapies for the treatment of pre-type 2 diabetics would be available (insulin sensitizers with improvement of the lipid profile), there is a lack of suitable diagnostics in order to be able to use these treatment options timely and in a targeted fashion.
Prior art techniques have also included method based on drawing a single blood sample, followed by measuring the blood glucose content and an NMR spectrum for determining the lipid profile, and final classification of the risk of type 2 diabetes by combining the parameters thus measured. However, the lipid profile is determined by numerous transient factors and possible correlation between lipid profile and diabetes can be established in an evidence-based fashion at best, i.e. based on populations and is not necessarily applicable to an individual case. Consequently, this method also provides no early diagnosis of pre-type 2 diabetes at the desired reliability.
It is therefore one of the object of the invention to devise a way of early detection of disturbances of glucose metabolism.
The present invention includes the collection of a large number of blood glucose concentration measuring values that are relatively closely spaced in time. However, unlike the methods described above, the present invention is not concerned with predicting future blood glucose concentration values or optimally controlling insulin administrations, but rather with the diagnosis of disturbances, in particular disease-related disturbances, of glucose metabolism.
Yet another object of the invention is a method for investigating the glucose metabolism of a human being for disease-relevant and/or disease-related particularities.
Yet another object of the invention is a system for investigating the glucose metabolism of a human being for disease-related particularities comprising a measuring unit for measuring the glucose concentration and an analytical unit for determining from the glucose concentration measuring values.
In the following, reference shall be made to the blood glucose concentration without limiting the scope of the invention. Since the invention relates to the processing of data points rather than the actual measuring of a glucose concentration, the glucose concentration of any other body fluid, for example interstitial fluid or eye fluid, that can be measured by spectroscopic means can be used just as well.
As part of the invention, it was noted that early anomalies of glucose metabolism are characterized by increasing disturbance of the body's intrinsic mechanism for regulation of the blood glucose concentration. From this, the inventors concluded that the particularities of the regulatory mechanisms that are relevant for diagnosis cannot be investigated by a single measurement or a measurement over a short period of time of only a few minutes, since this provides only a snapshot of the complex dynamics.
The blood glucose concentration of a human being varies during the course of the day and is strongly dependent on the intake of food and on physical exercise. For this reason, a single blood glucose concentration measuring value is often not indicative of whether it was measured on an ill or a healthy human being. Only the dynamics of the regulatory system allow disease-related particularities to be recognized reliably.
According to the invention, the blood glucose concentration is measured for a period of at least four hours, preferably at least six hours, such that typical changes in the blood glucose concentration such as those that occur in the course of the day, for example after meals, and associated responses of the body's intrinsic regulatory mechanism can be detected.
A further insight of the inventors was that particularities of the body's intrinsic regulatory mechanism are difficult to recognize in a customary representation, in which the blood glucose concentration is plotted against time, but show up clearly in a phase space representation both for the human eye and for mathematical evaluation algorithms. The data points are determined in phase space coordinates from the blood glucose concentration measuring values g(t1) to g(tn).
In a phase space, in control engineering sometimes referred to as “state space”, any possible state of a dynamic system can be represented by a point. For example, the phase space coordinates of a moving particle can comprises its location and momentum or its momentum and acceleration. It is an essential characteristic of a phase space that time is not a coordinate. The sequential states of the system over time form a line in phase space that is called trajectory and whose profile is characteristic of the dynamics of the system.
Obviously, a trajectory can be determined only by approximation in practical application, since the measuring values, on the one hand, are inevitably associated with measuring errors and, on the other hand, cannot be determined at infinite density. In the context of this application, trajectory shall be defined as a line in phase space that is determined from the data points and approximates the theoretical exact trajectory.
The so-called delay coordinates are another important example of phase space coordinates. In delay coordinates, the state of a dynamic system is characterized not by multiple state variables measured simultaneously (location and momentum of a particle, for example), but by multiple values of a single state variable measured at time points that differ from each other by a delay time τ.
Suitable phase space coordinates for the present invention are, for example, the blood glucose concentration g(t) and its rate of change g′(t) or delay coordinates g(t) and g(t-τ). If delay coordinates are to be used, it is best to select a delay time τ of between 10 minutes and 90 minutes, preferably between 15 minutes and 30 minutes.
Type 2 diabetes is a chronic metabolic disease that progresses through various stages. Each stage represents a certain pathological state of glucose metabolism and requires therapeutic measures that are specifically adapted to the manifest stage. A type 2 diabetes disease starts with disturbance of the body's intrinsic glucose level regulation mechanisms. This disturbance is manifested in the form of a slower counter-regulation upon food intake in combination with reduced initial insulin secretion by the pancreas. In the next stage, all endogenous insulin secretion upon food intake is reduced such that extensive hyperglycemias manifest. The endogenous insulin production is basically arrested in the subsequent stage such that the body's intrinsic regulation of the glucose level counteracts hypoglycemias only. In the final stage of the disease, even this endogenous regulatory mechanism is lost.
Various therapeutic measures are available for the treatment of these stages of type 2 diabetes, for example diet, oral medication to enhance the sensitivity to insulin, and insulin. The targeted use of these therapeutic measures requires so-called staging, i.e. a reliable diagnosis of the stage of disease that is manifest in the individual case. The present invention allows a reliable diagnosis to be made periodically such that individualized optimization of therapy in the context of staging is made possible.
Although existing diagnostic methods, such as measuring insulin secretion and insulin sensitivity, can be used for staging, the effort involved is prohibitive, not least because the individualized optimization of therapy implies the adaptation of the measures as often as possible.
The data points obtained upon application of the method according to the invention can be processed in a variety of ways in order to allow a physician to obtain a diagnosis more easily.
These and other features and advantages of the present invention will be more fully understood from the following detailed description of the invention taken together with the accompanying claims and drawings. It is noted that the scope of the claims is definitely by the recitations therein and not by the specific discussion of the features and advantages set forth in the present description.
Skilled artisans appreciate that elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions of some of the elements in the figure may be exaggerated relative to other elements to help improve understanding of the embodiment(s) of the present invention.